Dartmouth researchers identify multi-tasking circadian protein

HANOVER, N.H. -- Dartmouth Medical School geneticists have found a molecular shortcut from light reception to gene activation in their work to understand biological clocks. Their research has revealed that the protein called White Collar-1 does double duty: it perceives light and then, in response to light, directly turns on a key gene called frequency, which is a central component of the clock.

Biological clocks are molecularly driven and are set, or synchronized, by the daily cycles of light and dark. Using the fungus Neurospora, the Dartmouth team is studying how organisms keep track of time using this internal clock.

"What we have discovered is that a protein called White Collar-1 is both the photoreceptor and the mechanism that turns on the frequency gene, all in one molecule," explains Allan Froehlich, the lead author. "It's the combination of the two activities that is so interesting."

The findings, by Professors Jay Dunlap and Jennifer Loros, graduate student Allan Froehlich, and post-doctoral fellow Yi Liu, now on the faculty at the University of Texas Southwestern Medical Center, was published in the Aug. 2 issue of Science; the study was reported online in the July 4, 2002, issue of Sciencexpress. The Dunlap and Loros laboratories have made numerous contributions to understanding the genetic foundation for biological clocks.

Researchers, working with a variety of organisms, have already begun to understand how photoreceptor proteins perceive light at the molecular level and then pass on this information through a complex series of proteins. However, this finding with the White Collar-1 protein reveals a relatively simple process between a light-perceiving protein and turning on a gene.

"Virtually nothing is known about how pathogenic fungi respond to light or whether our discovery can be exploited for a noninvasive medical therapy," Dunlap says. "But, if you want to do therapy--antifungal, antibacterial or anything--you start looking for biochemical activities that the host does not have that can be targeted to the pathogen."

Froehlich, working with Dunlap and Loros, built on their discovery that the gene frequency encodes a central cog of the biological clock and that light resets the clock through frequency. He then determined that the clock proteins White Collar-1 and White Collar-2 bind to the specific parts of frequency that turn on frequency in response to light. And finally, he showed that under appropriate biochemical conditions WC-1 was the actual photoreceptor protein.

"The next step is to continue to understand how the proteins work," says Froehlich. "There are many more unidentified proteins that may be influencing biological clocks, which provides us with lots more to discover."

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